1. Field of the Invention
The present invention provides therapeutic agents for diabetes comprising a 2-(N-cyanoimino)thiazolidin-4-one derivative or a solvate or a pharmaceutically acceptable salt thereof as an active ingredient.
2. Description of the Related Art
Diabetes, recently mentioned as a representative example of life-style related diseases, is a disease that shows an acute symptom due to the remarkably high blood sugar or ketoacidosis, or various chronic, general metabolic abnormalities arising from a prolonged high blood sugar status or a decrease in glucose tolerance. The crisis of the diabetes has congenital genetic factors and acquired environmental factors such as eating habits and exercise levels. Both of them are mutually influenced, thus resulting in various types of diabetic crisis and various types of disease progress.
The pathogenic causes are insulin productive disorders, secretion disorders or reductions in activities and sensitivities of the secreted insulin. The diabetes is largely grouped into the following two types: insulin-dependent diabetes mellitus (also known as Type 1 diabetes) and non-insulin-dependent diabetes mellitus (also known as Type 2 diabetes). It is the latter insulin-nondependent diabetes a trend of which is a remarkable increase in a number of patients, and furthermore has a lot of diabetes.
The hyperlipidemia is mentioned as one of the life-style-related diseases as much as so for diabetes. The hyperlipidemia means status in which levels of lipids in plasma are increased over normal ranges. The lipids in the plasma are triglycerides, cholesterol, phospholipids, and free fatty acids. All conditions in which any one type of these lipids or multiple types have increased are designated as hyperlipidemia. Almost all lipids in the blood exist as lipoproteins combined with proteins. The free fatty acids in the blood are combined with albumin or lipoproteins; these complexes are also included in the concept of the lipoproteins in the present invention.
Diabetes has been recognized since ancient times, and diagnostic and therapeutic methods have been investigated for many years. As the oral hypoglycemic agents, sulfonylureas (for example, tolbutamide, chlorpropamide and glibenclamide), biguanides (for example, metformin and buformin) and xcex1-glucosidase inhibitors (for example, acarbose and voglibose) can be listed. In addition, recently the agents for insulin-resistance amelioration (for example, troglitazone, rosiglitazone and pioglitazone) have been developed and marketed. Thus, currently there are various types of therapeutic agents, however, still the patient number has been continuously increasing. Thus, the development of more efficient agents is anticipated.
Currently targets of diabetes therapies and controls are said to inhibit pathogenesis and progress of vascular complications that lead to serious problems, and to allow the diabetes patients have longevity and curability equivalent to normal subjects. Many diabetes patients tend to develop microangiopathy and macroangiopathy that are frequently associated with hypertriglyceridemia and hypercholesterolemia, risk factors of complications. However, because of pathogenic differences between diabetes, hypertriglyceridemia and hypercholesterolemia, different agents have been applied for the respective therapies.
For example, as a first choice for hypertriglyceridemia, dextran sulflate sodium, nicotinic acid derivatives or fibrates have been selected, and among them, bezafibrate has been well known. For hypercholesterolemia, HMG-CoA reductase inhibitors, referred as statins, such as pravastatin and simvastatin have been widely in clinical usage. Generally, when only a cholesterol level is high, HMG-CoA reductase inhibitors are used. However, the combined administration of HMG-CoA reductase inhibitors with fibrates or nicotinic acids gives rise to an increased risk of rhabdomyolysis.
It has been already known that dioxothiazolidine derivatives act for lowering blood sugar to some degree. 5-(Benzyl)thiazolidine-2,4-dione, reported 1971 by Taylor et al; AL-321 (Chemical name: 5-[4-(2-methyl-2-phenypropoxy)benzyl]thiazolidine-2,4-dione, Chem. Pharm. Bull., 30, 3580 (1980)) reported 1982 by Sohda et al; ciglitazone, which obtained as a result of a optimization of AL-321; troglitazone, rosiglitazone, and pioglitazone, which are chosen for clinical development from a large number of thiazolidine derivatives synthesized in many enterprises through design and structure-activity relationship analysis of ciglitazone analogue; for example. Any of AL-321, ciglitazone, troglitazone, rosiglitazone and pioglitazone has a 5-(benzyl)thiazolidine-2,4-dione moiety, a common structural unit. And recently troglitazone, rosiglitazone and pioglitazone were marketed as antidiabetic agents.
However, within a few months after troglitazone on market, adverse effects of severe hepatic symptoms, including death cases, were reported, thereby, monotherapy with this agent was considered to generate a high risk rather than antidiabetic effects. Thus, combined administration of three agents; troglitazone, sulfonylureas and biguanides, has been regarded desirable. When rosiglitazone or pioglitazone is administered, periodical blood tests to monitor liver function are required similar to the case of troglitazone. Developments of antidiabetic agents more excellent in efficacy and safety have been anticipated.
In Japanese Patent Application No. 1998-232216, the present inventor shows that novel 2-(N-cyanoimino)thiazolidin-4-one derivatives possess activities to improvement of the hyperlipidemia such as hypertriglyceridemia and hypercholesterolemia. By conducting intensive research, 2-(N-cyanoimino)thiazolidin-4-one derivatives were found to have blood sugar lowering effects as much as troglitazone in diabetes model animals, despite its structural difference from 5-(benzyl)thiazolidine-2,4-dione, the structure of which has been regarded desirable. Thus the present invention was successfully established.
In summary, the compounds of the present invention act for improving hyperlipidemia as well as diabetes, and these traits prevent from the two big risk factors of vascular disease, diabetes and hyperlipidemia simultaneously. This means that said compounds act synergically from both aspects of the diabetes and hyperlipidemia, for improvement in complications such as microangiopathy and macroangiopathy. The said compounds can be excellent therapeutic agents for diabetes extremely suit aims of the diabetes control and therapy xe2x80x9cprevention of pathogenesis and progression of vascular complications that evoke serious statesxe2x80x9d.
This invention provides therapeutic agents for diabetes comprising a 2-(N-cyanoimino)thiazolidine-4-one derivative represented by formula I or a solvate or a pharmaceutically acceptable salt thereof as an active ingredient. 
wherein ring A represents a benzene ring, a condensed ring or a heterocyclic ring, each of which may be substituted by one or more substituents selected from a straight or branched C1-C4 alkyl group, a haloalkyl group, a halogen atom or xe2x80x94OR5;
R1 represents a single bond, an oxygen atom, a sulfur atom, a methyne group, a straight or branched C1-C4 alkylene or alkenylene group optionally substituted by a phenyl group, R6xe2x80x94X, Xxe2x80x94R6, Xxe2x80x94R6xe2x80x94X, R6xe2x80x94Xxe2x80x94R6, xe2x80x94C(xe2x95x90O)xe2x80x94NR7xe2x80x94 or xe2x80x94NR7xe2x80x94C(xe2x95x90O)xe2x80x94;
R2 and R3 are the same or different and each represents a hydrogen atom, a C1-C4 alkyl group, xe2x80x94OR8 or a halogen atom;
R4 represents a hydrogen atom or a C1-C4 alkyl group,
R5 represents a hydrogen atom or a C1-C4 alkyl group;
R6 represents a straight or branched C1-C4 alkylene or alkenylene group;
R7 represents a hydrogen atom or a C1-C4 alkyl group;
R8 represents a hydrogen atom, a C1-C4 alkyl group or an aralkyl group;
X represents an oxygen atom or a sulfur atom;
the configuration of the exocyclic methylene group at 5-position of the thiazolidine ring includes both E- and Z-configuration.
The term therapeutic agents for diabetes of the present invention means the agents administered to diabetes-prone subjects, that is, prophylactic agents as well as the agents for treatment of diabetes patients.
xe2x80x9cSaltsxe2x80x9d refers to low toxic salts derived from sodium, potassium, ammonia or organic amines, for instance.
xe2x80x9cC1-C4 alkyl groupxe2x80x9d refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl or tert-butyl, for instance.
xe2x80x9cC1-C4 alkoxy groupxe2x80x9d refers to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or tert-butoxy, for instance.
xe2x80x9chalogen atomxe2x80x9d refers to generally fluorine atom, chlorine atom, bromine atom, or iodine atom. More preferably it is fluorine atom or chlorine atom.
xe2x80x9cring Axe2x80x9d refers to a benzene ring, a benzodioxole ring, a benzofuran ring, a benzothiazole, a fluorene ring, an indan ring, an indoline ring or a pyridine ring, connecting with R1 at any position, for instance.
The compounds of the present invention can be obtained in accordance with the method described in Japanese Patent Application No. 1998-232216, for instance. There are geometric isomers for these compounds, however, in solution, reversible isomerization of the exocyclic methylene group at 5-position of the thiazolidine ring occurs very easily by the action of light or heat.
Particularly preferred compounds represented by formula I are as follows;
2-(N-Cyanoimino)-5-[(E)-4-styrylbenzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(xcex1-methylstyryl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(benzyloxymethyl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(xcex2-methylstyryl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(3-phenylpropoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-chlorophenoxy)benzylidene]thiazolidine-4-one;
2-(N-Cyanoimino)-5-(4-phenylthiobenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(2-fluorostyryl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(2,5-dimethylphenoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(2-phenylpropoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(3-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(benzyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(5-chlorobenzofuran-2-yl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-4-(4-methoxystyryl)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(3-phenoxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(1,3-benzodioxole-5-ylmethoxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(4-methylbenzyloxy)benzylidene]thiazolidin-4-one,
2-(N-Cyanoimino)-5-[4-(4-chlorobenzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[3-methoxy-(E)-4-styrylbenzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(2-phenethyloxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenoxybenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[3-(benzyloxy)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-(benzylthio)benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-phenethylbenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[4-[2-(4-chlorophenyl)ethoxy]benzylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-[1-[(E)-4-(4-methoxystyryl)phenyl]ethylidene]thiazolidin-4-one;
2-(N-Cyanoimino)-5-(4-benzyloxy-2, 5-dimethylbenzylidene)thiazolidin-4-one;
2-(N-Cyanoimino)-5-[(E)-3-styrylbenzylidene]thiazolidin-4-one.
The compounds of the present invention and pharmaceutically acceptable salts thereof can be orally or parenterally administered either alone or generally in the form of appropriate pharmaceutical compositions such as tablets, powders, granules, capsules, syrups, or injections comprised of pharmaceutically acceptable carriers, diluents, solubilizers, or other pharmaceutical additives. Oral administration is preferred. Among these preparations, oral administration preparations are particularly preferable.
The dosage will depend on the condition, age, body weight, and other factors of each patient or efficacy of an active ingredient. Generally, when the compound of the present invention is orally administered, the daily dose of the present invention preferably ranges from 10 to 2000 mg, more preferably from 100 to 1000 mg for adult, and is administered once or in several divided doses a day.